Over the past few months, I’ve had numerous conversations at work and conferences about particulates in cell and gene therapies. These discussions have highlighted to me two things. Firstly, the importance of identifying both inorganic and organic particulates in cell-based therapies. Secondly, many in the field may not be fully aware of the existing options for this identification, which has significant implications for the quality and safety of these advanced therapies.
Challenges in Cell-based Therapeutic Products
Building on these insights, it’s clear that manufacturing finished products for cell-based therapies presents unique challenges. These therapies often involve living cells, introducing complexities not found in traditional pharmaceuticals. The additional complexity arises from the presence of living cells and their surrounding secretome. For some therapeutics, this secretome is essential for their function and naturally contains organic particulates. Despite these complexities, ensuring the purity and integrity of these products is crucial, as any contaminants, including particulates, can significantly impact their efficacy and safety.
Another challenge caused by the presence of living cells and their surrounding secretome is that it is often not possible to test finished product for sub-visible particles. Therefore, it is essential that a baseline for sub-visible and visible particulate levels is established. To create a baseline, a comprehensive suite of testing of all materials and processes involved in the manufacture of finished product is typically performed. To ensure that the whole manufacturing process is tested, a mock run where the entire manufacturing process without growing cells allows the flushed fluid to be tested for particulates. At this stage, sub-visible, visible and even endotoxin testing may be performed. The data from this mock run helps in understanding the typical levels of particulates present, assessing the risk each component poses and implementing strategies to control this risk. It will also give the reassurance and confidence that baseline particulate levels are acceptable before the actual product is processed.
While the complexity of a cell-based therapeutic poses challenges when assessing particulates in the final product, in addition to establishing a baseline level generated by the manufacturing process, incoming raw materials should still be assessed for particulates. The materials used to produce the therapeutic will vary but often include common reagents such as DMSO, DPBS, and EDTA. These reagents should be assessed for particulates upon arrival and by screening the reagents before they are used in the manufacturing process means that additional particulates are not being introduce into the process.
When the likely particulate level produced during a manufacturing run has been determined, incoming raw materials analysed, and the risk is at a low and acceptable level. The finished product would still need to be assess for the presence of any visible foreign bodies. During this analysis, any extrinsic object in the samples should be investigated. Often these bodies are a fibrous material and could contain protein, silicone and non-silicone based plastics or a range of all three. Identifying these foreign bodies are crucial as they may be indicative of a fault or contamination occurring during the manufacturing process.
